A team of UC Davis investigators, led by Christopher P. Evans, professor and chair of the Department of Urology, has received a $660,000 grant from the U.S. Department of Defense to study a promising new approach for treating advanced prostate cancer.

The strategy involves combining an experimental anti-cancer drug with another agent that they expect will enhance its effectiveness. The drugs are believed to target underlying processes that lead to castration-resistant prostate cancer, the most deadly form of the disease, and may be applicable to other types of cancer.

Christopher P. Evans

"We are very grateful for this opportunity to explore a novel approach for treating prostate cancer," said Evans. "This strategy, which involves overcoming a tumor's resistance to current cancer therapies, shows great promise for benefitting patients with advanced disease.

Early in the disease process, prostate cancer cells are dependent on the male hormone, testosterone. Standard therapy for prostate cancer, known as "androgen ablation" or "chemo-castration," involves blocking the body's testosterone by either hormone therapy or by removing the testicles. However, the treatment is only temporarily effective because after some time, prostate cancer cells "escape" their dependence on testosterone and promote cancer cell growth despite the absence of testosterone. The resulting castration-resistant cancer becomes metastatic, frequently traveling to bone.

The first part of the novel strategy involves targeting a group of proteins known as tyrosine kinases, which are especially active in cancer cells and when present, indicate that healthy cellular processes have gone awry. One type of tyrosine kinase, known as Src (pronounced "sark") kinase, activates a prostate cell's androgen receptors and promotes tumor growth, even in the absence of testosterone.

Evans' team has been investigating an experimental drug known as saracatinib (AZD0530), which acts as a Src kinase inhibitor. Although they found in clinical trials that the drug blocks cancer spread, it was less effective in actually killing tumor cells. This led them to develop a second approach to enhance the potency of Src kinase inhibitors.

With this grant, the investigators are focusing on manipulating a natural process called autophagy, which cells normally utilize for growth, development and maintenance. Autophagy involves breaking down old proteins and recycling their components to use for energy. For cells under stress, it is an important mechanism for reallocating nutrients and enhancing survival.

When treating a cancer patient with saracatinib, cancer cells become stressed because of their dependence on Src kinase for metabolic activity, and turn on the autophagy process, allowing them to survive. Normal cells, being less dependent on Src kinase, do not activate autophagy to the same extent.

The research will make use of chloroquine, a drug that has been used for decades to treat malaria, and which happens to also "turns off" autophagy, disrupting a cell's ability to break down old proteins.

Hsing-Jien Kung

"Autophagy appears to be an important process that is preferentially upregulated in cancer cells during cancer therapy, making treatment less effective," said Evans. "By overcoming autophagy, we hope to 'starve' cancer cells, making them more susceptible to being killed."

The investigators plan to treat cellular cultures of prostate cancer as well as mouse models of the disease with the combination saracatinib-chloroquine treatment. This research is expected to lead to applying this innovative approach in clinical trials with prostate cancer patients.

"Many different cancers are "addicted" to tyrosine kinase pathways, and tyrosine kinase inhibitors have been widely used for treatment of cancers," said Hsing-Jien Kung, a collaborator on the study and professor of biochemistry and molecular medicine at UC Davis. "We believe that this two-pronged strategy can be generalized to other treatments as well. This is a novel approach with great potential."

UC Davis Comprehensive Cancer CenterUC Davis Comprehensive Cancer Center is the only National Cancer Institute-designated center serving the Central Valley and inland Northern California, a region of more than 6 million people. Its specialists provide compassionate, comprehensive care for more than 9,000 adults and children every year, and access to more than 150 clinical trials at any given time. Its innovative research program engages more than 280 scientists at UC Davis, Lawrence Livermore National Laboratory and Jackson Laboratory (JAX West), whose scientific partnerships advance discovery of new tools to diagnose and treat cancer. Through the Cancer Care Network, UC Davis collaborates with a number of hospitals and clinical centers throughout the Central Valley and Northern California regions to offer the latest cancer care. Its community-based outreach and education programs address disparities in cancer outcomes across diverse populations. For more information, visit cancer.ucdavis.edu.